Regulatory role of KEAP1 and NRF2 in PPARγ expression and chemoresistance in human non-small-cell lung carcinoma cells.
Regulatory role of KEAP1 and NRF2 in PPARγ expression and chemoresistance in human non-small-cell lung carcinoma cells.
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DOI：
10.1016/j.freeradbiomed.2012.05.041
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发表时间：
2012-08-15
影响因子：
7.4
通讯作者：
Pi, Jingbo
中科院分区：
文献类型：
--
作者：
Zhan, Lijuan;Zhang, Hao;Zhang, Qiang;Woods, Courtney G.;Chen, Yanyan;Xue, Peng;Dong, Jian;Tokar, Erik J.;Xu, Yuanyuan;Hou, Yongyong;Fu, Jingqi;Yarborough, Kathy;Wang, Aiping;Qu, Weidong;Waalkes, Michael P.;Andersen, Melvin E.;Pi, Jingbo
核因子E2相关因子2（NRF2）是细胞防御氧化应激和化学解毒的主要调节因子。然而，由NRF2突变和/或其抑制因子Kelch样ECH相关蛋白1（KEAP 1）的下调或突变引起的NRF2的持续激活与非小细胞肺癌（NSCLC）的致瘤性和化疗耐药性相关。因此，抑制NRF2介导的适应性抗氧化反应被广泛认为是一种有前途的策略，以防止肿瘤生长和逆转非小细胞肺癌的化疗耐药性。出乎意料的是，通过慢病毒shRNA稳定敲除KEAP 1使三种独立的NSCLC细胞系（A549、HTB-178和HTB-182）对多种化疗剂敏感，包括三氧化二砷（As2O3）、依托泊苷和多柔比星，尽管NRF 2水平适度增加。在肺腺癌上皮A549细胞中，KEAP 1的沉默增加了过氧化物酶体增殖物激活受体γ（PPAR γ）和与细胞分化相关的基因（包括E-Cadherin和Gelsolin）的表达。此外，KEAP 1敲除的A549细胞显示原癌基因Cyclin D1和癌症干细胞（CSC）标记物的表达减弱，并减少非粘附球体形成。此外，KEAP 1的缺陷导致响应于As2O3的PPAR γ的诱导升高。用PPAR γ激动剂预处理A549细胞可激活PPAR γ，增强As2O3的细胞毒性。一个数学模型被制定来提出一个假设，即KEAP 1和NRF 2对PPAR γ和解毒酶的差异调节可能支持所观察到的化学敏感性的景观变化。总的来说，KEAP 1在人NSCLC细胞中表达的抑制导致对化疗药物的敏感性，这可能归因于PPAR γ的激活以及随后细胞分化和CSC丰度的改变。
The nuclear factor-E2-related factor 2 (NRF2) serves as a master regulator in cellular defense against oxidative stress and chemical detoxification. However, persistent activation of NRF2 resulting from mutations of NRF2 and/or downregulation or mutations of its suppressor Kelch-like ECH-associated protein 1 (KEAP1) are associated with tumorigenicity and chemoresistance of non-small-cell lung carcinomas (NSCLCs). Thus, inhibiting NRF2-mediated adaptive antioxidant response is widely considered a promising strategy to prevent tumor growth and reverse chemoresistance in NSCLCs. Unexpectedly, stable knockdown of KEAP1 by lentiviral shRNA sensitized three independent NSCLC cell lines (A549, HTB-178 and HTB-182) to multiple chemotherapeutic agents, including arsenic trioxide (As2O3), etoposide and doxorubicin, despite moderately increased NRF2 levels. In lung adenocarcinoma epithelial A549 cells, silencing of KEAP1 augmented the expression of peroxisome proliferator-activated receptor γ (PPARγ) and genes associated with cell differentiation, including E-Cadherin and Gelsolin. In addition, KEAP1-knockdown A549 cells displayed attenuated expression of proto-oncogene Cyclin D1 and markers for cancer stem cells (CSCs), and reduced non-adherent sphere formation. Moreover, deficiency of KEAP1 led to elevated induction of PPARγ in response to As2O3. Pretreatment of A549 cells with PPARγ agonists activated PPARγ and augmented the cytotoxicity of As2O3. A mathematical model was formulated to advance a hypothesis that differential regulation of PPARγ and detoxification enzymes by KEAP1 and NRF2 may underpin the observed landscape changes in chemo-sensitivity. Collectively, suppression of KEAP1 expression in human NSCLC cells resulted in sensitization to chemotherapeutic agents, which may be attributed to activation of PPARγ and subsequent alterations in cell differentiation and CSC abundance.
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DOI：
10.1073/pnas.95.15.8806
发表时间：
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影响因子：
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作者：
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